Effectiveness of management strategies for uninvestigated dyspepsia: systematic review and network meta-analysisBMJ 2019; 367 doi: https://doi.org/10.1136/bmj.l6483 (Published 11 December 2019) Cite this as: BMJ 2019;367:l6483
All rapid responses
Since their introduction, prescriptions for proton pump inhibitors (PPIs) have doubled in the United Kingdom and United States. (1,2) More particularly omeprazole makes up for about four fifths of all prescriptions. (1) It is approximated that 90% of the NHS drug budget goes towards treating dyspepsia. (1) However, this can be corrected if medications are limited to advised recommendations. (1) A study conducted revealed that 67% of inpatients in the UK did not meet recommended criteria for receiving PPIs. (1) Studies published in recent years have reported adverse events associated with the use of PPIs alone. A review of the literature revealed the following adverse outcomes:
1. Meta-Analysis of 9 observational studies revealed that 43% of the 109,798 patients were at increased risk of hypomagnesemia. (2)
2. PPIs tend to predispose the patient to small intestinal bacterial overgrowth (SIBO) by decreasing gastric acid production. Meta-Analysis of 11 studies revealed an increased risk of developing SIBO in PPI users when compared with non users (OR, 2.28; 95% CI, 1.24-4.21). (2)
3. Patients receiving PPIs for more than 2 years were at a 65% increased risk of vitamin B12 deficiency. (2) It was also noted that the use of 1.5 pills or more per day was also associated with increased risk of vitamin B12 deficiency (odds ratio [OR], 1.95; 95% CI, 1.77-2.15). (2) This is due to the fact that decreased gastric acid does not facilitate absorption of vitamin B12 in the terminal ileum.
4. PPIs predispose to Clostridium difficile induced colitis. A meta-analysis of 42 observational studies revealed an increased risk of both incident and recurring cases (OR, 1.74; 95% CI, 1.47-2.85 and OR, 2.51; 95% CI, 1.16-5.44, respectively). (1,2) It is also important to note that the H2 receptor antagonists may also cause Clostridium difficile induced colitis, but the risk is relatively lower than with the use of PPIs.
5. Increased risk of dementia because PPIs increase amyloid synthesis and decrease its degradation in the brain. (2) A prospective cohort study of 73,679 individuals by Gomm et al revealed a 44% risk of dementia with the use of PPIs.
6. Multiple studies have also shown increased risk of fractures with the use of PPIs. The highest risk is associated with spine fracture 58% (RR, 1.58; 95% CI, 1.38-1.82). (2) Fracture risk were also reported with any site (33% (RR, 1.33; 95% CI, 1.15-1.54)) and the hip (26% (RR, 1.26; 95% CI, 1.16-1.36)). (2)
7. Greater risk of acquiring both Acute kidney injury (64%) and Chronic kidney disease (50%). (2) Furthermore, a population based study of patients older than 65 years of age found a 2.5-times increase in the risk of developing AKI and three times the risk for acute interstitial nephritis. (2)
8. Several studies have also shown a 27% increased risk of developing community accquired pneumonia with the use of PPIs. (2)
1. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ (Clinical Research ed.). 2008 Jan;336(7634):2-3.
2. Nehra AK, Alexander JA, Loftus CG, Nehra V. Proton Pump Inhibitors: Review of Emerging Concerns. Mayo Clinic Proceedings. 2018 Feb;93(2):240-246
Competing interests: No competing interests
Re: Effectiveness of management strategies for uninvestigated dyspepsia: systematic review and network meta-analysis
We were puzzled by the rationale for Dr. Saripanidis's comments. Among the included trials of empirical acid suppression therapy in this network meta-analysis , (1) none used a treatment duration of longer than 8 weeks, so the trials were not studying the efficacy of long-term proton pump inhibitor (PPI) use in uninvestigated dyspepsia, nor were they advocating it. In addition, in the network meta-analysis empirical acid suppression was ranked lower, in terms of both effect on symptoms and likelihood of receiving endoscopy, than "test and treat", (1) so the results could not be used to argue for long-term PPI use as a strategy for uninvestigated dyspepsia either. Even among patients in the “test and treat” arms of included trials who were H. pylori-negative, the maximum duration of PPI therapy was 4 weeks, and in five of these trials this patient group received no PPI treatment whatsoever as part of their initial management strategy. (2-6)
Of the myriad of apparent adverse outcomes with which PPIs are provisionally linked, and which Dr. Saripanidis alludes to, many lack any plausible biological rationale, and are derived from secondary analyses of huge pharmacy claims databases, never designed for this purpose. (7) These almost exclusively retrospective data are prone to bias and confounding that cannot be completely controlled for. Against all of these weak and inconclusive data must be weighed the results of a large randomised controlled trial published recently. (8) Among 17,598 patients randomised to rivaroxaban, aspirin, or the combination of both drugs, those not already on a PPI were further randomised to pantoprazole 40 mg or placebo once-daily and followed prospectively for a median of three years, resulting in 53,152 patient-years of follow up. In this trial, when used for 3 years, pantoprazole was not associated with any adverse event, with the possible exception of an increased risk of enteric infections.
We agree that PPIs should only be used when medically necessary, and that the duration of their use should be minimised. The results of our network meta-analysis of management strategies for uninvestigated dyspepsia actually support this. (1)
1. Eusebi LH, Black CJ, Howden CW, Ford AC. Effectiveness of management strategies for uninvestigated dyspepsia: Systematic review and network meta-analysis. BMJ 2019; 367: l6483.
2. Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test and eradicate versus prompt endoscopy for management of dyspeptic patients: A randomised trial. Lancet 2000; 356: 455-60.
3. McColl KEL, Murray LS, Gillen D, et al. Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H. pylori testing alone in the management of dyspepsia. BMJ 2002; 324: 999-1002.
4. Arents NLA, Thijs JC, van Zwet AA, et al. Approach to treatment of dyspepsia in primary care: A randomized trial comparing 'test and treat' with prompt endoscopy. Arch Intern Med 2003; 163(13): 1606-12.
5. Jarbol DE, Kragstrup J, Stovring H, Havelund T, Schaffalitzky de Muckadell OB. Proton pump inhibitor or testing for Helicobacter pylori as the first step for patients presenting with dyspepsia? A cluster-randomized trial. Am J Gastroenterol 2006; 101: 1200-8.
6. Mahadeva S, Chia YC, Vinothini A, Mohazmi M, Goh KL. Cost-effectiveness of and satisfaction with a Helicobacter pylori "test and treat" strategy compared with prompt endoscopy in young Asians with dyspepsia. Gut 2008; 57: 1214-20.
7. Vaezi MF, Yang YX, Howden CW. Complications of proton pump inhibitor therapy. Gastroenterology 2017; 153: 35-48.
8. Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 2019; 157: :682-91.
Competing interests: No competing interests
Patients who received the following proton pump inhibitors (PPIs) as monotherapy, compared to patients who received histamine-2 receptor antagonists (H2RAs), had a significant:
increase in the frequency of Acute Kidney Injury: omeprazole (OR 5.8), esomeprazole (OR 3.3), pantoprazole (OR 1.8), lansoprazole (OR 10.8)
increase in the frequency of Chronic Kidney Disease: omeprazole (OR 18.1), esomeprazole (OR 29.9), lansoprazole (OR 154.9)
increase in the frequency of End Stage Renal Disease: omeprazole (OR 30.1), esomeprazole (OR 34.7), lansoprazole (OR 97.6)
increase in the frequency of Nephrolithiasis: omeprazole (OR 3.4), esomeprazole (OR 2.4), pantoprazole (OR 3.3), lansoprazole (OR 3.9)
increase in the frequency of Renal Impairment: omeprazole (OR 11.5), esomeprazole (OR 7.9), pantoprazole (OR 2.9), lansoprazole (OR 5.0), rabeprazole (OR 12.4)
increase in the frequency of hypomagnesemia: omeprazole (OR 224.6), esomeprazole (OR 30.2), pantoprazole (OR 115.4), lansoprazole (OR 82.4), rabeprazole (OR 151.9)
increase in the frequency of hypocalcemia: omeprazole (OR 75.3), esomeprazole (OR 10.0), pantoprazole (OR 21.7), lansoprazole (OR 41.2), rabeprazole (OR 28.9)
increase in the frequency of hypokalemia: omeprazole (OR 15.8), esomeprazole (OR 3.1), pantoprazole (OR 6.4), lansoprazole (OR 11.0), rabeprazole (OR 2.3)
increase in the frequency of hyponatremia: omeprazole (OR 7.0), pantoprazole (OR 2.0), lansoprazole (OR 4.0), rabeprazole (OR 4.3)
An extensive epidemiological study on 8.2 million people with 39,180,151 years of follow-up revealed that gastric acid-inhibiting substances, like PPIs, quintupled allergic symptoms in >60 year old patients.
Patients assuming PPIs had a significant increase in morbidity and mortality due to cardiovascular disease, in a systematic review of 37 studies.
Competing interests: No competing interests